Synthesis, and pharmacological evaluation of iminoguanidine derivatives: Identification of FuBIG showing protective effects against diabetic neuroinflammation with a favorable lactate metabolism profile

Diabetic neuroinflammation is a common and challenging complication of diabetes, recognized as a key factor triggering neuropathic damage during the progression of the disease. This study focuses on the inhibitory effects of iminoguanidine derivatives on diabetic neuroinflammation and their potential mechanisms. Preliminary screening showed that most derivatives did not promote lactate accumulation in LPS-induced SH-SY5Y or THLE-2 cells. Notably, 2,5-furan-bis(iminoguanidine) (FuBIG) modulated L-LDH activity and reduced lactic acid production. The anti-inflammatory activities of the target compounds were evaluated in LPS-induced BV2 and SH-SY5Y cells. Among them, FuBIG emerged as the most potent derivative, exhibiting protective effects with EC₅₀ values of 222.3 μM and 198.1 μM, respectively-superior to that of metformin (362.5 μM). In vitro studies showed that FuBIG enters THLE-2 cells via organic cation transporter 1 (OCT1). Further in vivo experiment displayed that FuBIG effectively metabolic disturbances in diabetic mice, reducing LDL-C, ALT, and AST levels while increasing HDL-C. In addition, mechanistic studies revealed that FuBIG activated the AMPK pathway in LPS-induced BV2 cells, suppressing pro-inflammatory cytokines, reducing ROS production, and preserving mitochondrial membrane potential to exert diverse beneficial effects. Furthermore, FuBIG inhibited neuronal Apoptosis by up-regulating anti-apoptotic protein Bcl-2 and down-regulating pro-apoptotic proteins Bax and Caspase-3. Pharmacokinetic and stability assessments further revealed that FuBIG exhibits exceptional metabolic stability in both plasma and liver microsomes, with a favorable in vivo half-life (t₁/₂ ≈ 4.1 h). Collectively, these findings highlight FuBIG-like iminoguanidine derivatives as promising lead compounds for treating diabetic neuroinflammation, warranting further investigation into the pharmacological mechanisms and therapeutic potential.

Antidiabetic drugs; Iminoguanidine; Lactic acidosis; Neuropathy.